A number of immunologically mediated skin diseases and immunologically mediated systemic disorders with cutaneous manifestations are now recognized as distinct entities with consistent clinical, histologic, and immunopathologic findings. Clinically, these disorders are characterized by morbidity (pain, pruritus, disfigurement) and, in some instances, by mortality (largely due to loss of epidermal barrier function and/or secondary infection). The major features of the more common immunologically mediated skin diseases are summarized in this chapter (Table 54-1) as are the systemic disorders with cutaneous manifestations.
Table 54-1 Immunologically Mediated Blistering Diseases
| Save Table
Table 54-1 Immunologically Mediated Blistering Diseases
|Pemphigus foliaceus||Crusts and shallow erosions on scalp, central face, upper chest, and back||Acantholytic blister formed in superficial layer of epidermis||Cell surface deposits of IgG on keratinocytes||Dsg1|
|Pemphigus vulgaris||Flaccid blisters, denuded skin, oromucosal lesions||Acantholytic blister formed in suprabasal layer of epidermis||Cell surface deposits of IgG on keratinocytes||Dsg3 (plus Dsg1 in patients with skin involvement)|
|Paraneoplastic pemphigus||Painful stomatitis with papulosquamous or lichenoid eruptions that progress to blisters||Acantholysis, keratinocyte necrosis and vacuolar interface dermatitis||Cell surface deposits of IgG and C3 on keratinocytes and (variably) similar immunoreactants in epidermal BMZ||Plakin protein family members and desmosomal cadherins (see text for details)|
|Bullous pemphigoid||Large tense blisters on flexor surfaces and trunk||Subepidermal blister with eosinophil-rich infiltrate||Linear band of IgG and/or C3 in epidermal BMZ||BPAG1, BPAG2|
|Pemphigoid gestationis||Pruritic, urticarial plaques, rimmed by vesicles and bullae on the trunk and extremities||Teardrop-shaped, subepidermal blisters in dermal papillae; eosinophil-rich infiltrate||Linear band of C3 in epidermal BMZ||BPAG2 (plus BPAG1 in some patients)|
|Linear IgA disease||Pruritic small papules on extensor surfaces; occasionally larger, arciform blisters||Subepidermal blister with neutrophil-rich infiltrate||Linear band of IgA in epidermal BMZ||BPAG2 (see text for specific details)|
|Cicatricial pemphigoid||Erosive and/or blistering lesions of mucous membranes and possibly the skin; scarring of some sites||Subepidermal blister that may or may not include a leukocytic infiltrate||Linear band of IgG, IgA, and/or C3 in epidermal BMZ||BPAG2, laminin-332, or others|
|Epidermolysis bullosa acquisita||Blisters, erosions, scars, and milia on sites exposed to trauma; widespread, inflammatory, tense blisters may be seen initially||Subepidermal blister that may or may not include a leukocytic infiltrate||Linear band of IgG and/or C3 in epidermal BMZ||Type VII collagen|
|Dermatitis herpetiformis||Extremely pruritic small papules and vesicles on elbows, knees, buttocks, and posterior neck||Subepidermal blister with neutrophils in dermal papillae||Granular deposits of IgA in dermal papillae||Epidermal transglutaminase|
Pemphigus refers to a group of autoantibody-mediated intraepidermal blistering diseases characterized by loss of cohesion between epidermal cells (a process termed acantholysis). Manual pressure to the skin of these patients may elicit the separation of the epidermis (Nikolsky's sign). This finding, while characteristic of pemphigus, is not specific to this group of disorders and is also seen in toxic epidermal necrolysis, Stevens-Johnson syndrome, and a few other skin diseases.
Pemphigus vulgaris (PV) is a mucocutaneous blistering disease that predominates in patients >40 years. PV typically begins on mucosal surfaces and often progresses to involve the skin. PV is characterized by fragile, flaccid blisters that rupture to produce extensive denudation of mucous membranes and skin (Fig. 54-1). PV typically involves the mouth, scalp, face, neck, axilla, groin, and trunk. PV may be associated with severe skin pain; some patients experience pruritus as well. Lesions usually heal without scarring, except at sites complicated by secondary infection or mechanically induced dermal wounds. Postinflammatory hyperpigmentation is usually present at sites of healed lesions for some time.
Pemphigus vulgaris. A. Pemphigus vulgaris demonstrating flaccid bullae that are easily ruptured, resulting in multiple erosions and crusted plaques. B. Pemphigus vulgaris almost invariably involves the oral mucosa and may present with erosions involving the gingiva, buccal mucosa, palate, posterior pharynx, or the tongue. (B, Courtesy of Robert Swerlick, MD;with permission.)
Biopsies of early lesions demonstrate intraepidermal vesicle formation secondary to loss of cohesion between epidermal cells (i.e., acantholytic blisters). Blister cavities contain acantholytic epidermal cells, which appear as round homogeneous cells containing hyperchromatic nuclei. Basal keratinocytes remain attached to the epidermal basement membrane; hence, blister formation is within the suprabasal portion of the epidermis. Lesional skin may contain focal collections of intraepidermal eosinophils within blister cavities; dermal alterations are slight, often limited to an eosinophil- predominant leukocytic infiltrate. Direct immunofluorescence microscopy of lesional or intact patient skin shows deposits of IgG on the surface of keratinocytes; deposits of complement components are typically found in lesional but not uninvolved skin. Deposits of IgG on keratinocytes are derived from circulating autoantibodies directed against cell-surface autoantigens. Such circulating autoantibodies can be demonstrated in 80–90% of PV patients by indirect immunofluorescence microscopy; monkey esophagus is the optimal substrate for these studies. Patients with PV have IgG autoantibodies directed against desmogleins (Dsgs), transmembrane desmosomal glycoproteins that belong to the cadherin family of calcium-dependent adhesion molecules. Such autoantibodies can be precisely quantitated by enzyme-linked immunosorbent assay (ELISA). Patients with early PV (i.e., mucosal disease) have IgG autoantibodies directed against Dsg3; patients with advanced PV (i.e., mucocutaneous disease) have IgG autoantibodies directed against both Dsg3 and Dsg1. Experimental studies have shown that autoantibodies from patients with PV are pathogenic (i.e., responsible for blister formation) and that their titer correlates with disease activity. Recent studies have shown that the anti-Dsg autoantibody profile in these patients' sera as well as the tissue distribution of ...